New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.

As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.

The clinical impact of IKZF1 mutation in acute myeloid leukemia.

Genetic heterogeneity poses a great challenge to the understanding and management of acute myeloid leukemia (AML). Knowledge of the IKZF1 mutation in AML specifically is extremely limited. In a previous work, we described the distribution pattern of IKZF1 mutation in AML, but its clinical impact has remained undefined due to the limited number of cases. Herein, we attempt to answer this question in one relatively large cohort covering 522 newly diagnosed AML patients. A total of 26 IKZF1 mutations were found in 20 AML patients (20/522, 3.83%). This condition has a young median age of onset of morbidity (P = 0.032). The baseline characteristics of IKZF1-mutated and wild-type patients were comparable. IKZF1 mutation showed significant co-occurrences with CEBPA (P < 0.001), SF3B1 (P < 0.001), and CSF3R (P = 0.005) mutations, and it was mutually exclusive with NPM1 mutation (P = 0.033). Although IKZF1-mutated AML was more preferably classified into the intermediate-risk group (P = 0.004), it showed one inferior complete remission rate (P = 0.032). AML with high burden of IKZF1 mutation (variant allele frequency > 0.20) showed relatively short overall survival period (P = 0.012), and it was an independent factor for the increased risk of death (hazard ratio, 6.101; 95% CI 2.278-16.335; P = 0.0003). In subgroup analysis, our results showed that IKZF1 mutation conferred poor therapeutic response and prognosis for SF3B1-mutated AML (P = 0.0017). We believe this work improves our knowledge of IKZF1 mutation.

γ-Catenin Overexpression in AML Patients May Promote Tumor Cell Survival via Activation of the Wnt/ß-Catenin Axis.

BACKGROUND: Canonical Wnt/ß-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. γ-catenin was previously demonstrated to be associated with the nuclear localization of ß-catenin, the central mediator, and to exert oncogenic effects in AML; however, the underlying mechanisms remain unclear. Our study aimed to investigate the expression characteristics of γ-catenin in AML patients, explore the mechanisms by which γ-catenin regulates ß-catenin, and discuss the feasibility of targeting γ-catenin for AML treatment. METHODS: The mRNA expression levels of γ-catenin in AML patients were measured by qRT-PCR. Cell proliferation was examined via Cell Counting Kit-8 (CCK-8) assays. The expression levels of related proteins were measured via Western blotting. Specific siRNA was used to modulate the expression level of the γ-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of γ-catenin and ß-catenin was examined via immunofluorescence with a confocal laser scanning microscope. RESULTS: Overexpression of γ-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of γ-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked ß-catenin nuclear translocation. Interestingly, γ-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited ß-catenin nuclear localization. Moreover, our data implied the relationship between γ-catenin and GSK3ß (whose effect on ß-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of γ-catenin inhibition. CONCLUSION: Taken together, our results revealed a potential role of γ-catenin in AML pathogenesis-mainly through the inhibition of GSK3ß-mediated nuclear localization of ß-catenin-and indicate that targeting γ-catenin might offer new AML treatments.